Small molecule anti-tumor agents used clinically often display poor pharmacokinetics, undesired toxicity and side-effects, and poor water solubility that present delivery difficulties. Numerous chemotherapeutic drugs used today have a relatively low therapeutic index, or therapeutic ratio, described as the lethal dose divided by the therapeutic dose (LD50/ED50). In essence, therapeutic benefits are often substantially offset by detrimental side effects.
Conjugation of chemotherapeutics to water-soluble polymers could greatly enhance their aqueous solubility as well as ease of administration, and further reduce side effects towards improving therapeutic efficacy by altering pharmacokinetics. The underlying in vivo characteristics of polymer drugs that lead to their beneficial effects are described by the enhanced permeation and retention (EPR) effect, which provides for a passive and selective uptake of the polymer-bound drugs into tumor tissue, and retention in that tissue due to a characteristic poor lymphatic drainage. (Maeda, et al. J. Control. Release 2000, 65 (1-2), 271-284.)
Effective polymer therapeutics require the use of biocompatible polymers with high water solubility and biocompatibility. Poly(ethylene glycol) (PEG) has been conjugated to various therapeutic protein and peptide drugs to enhance their therapeutic efficacy, such as erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), and interferon (IFN). PEGylation increases the apparent size of the proteins and peptides (thereby reducing the rate of renal clearance), shields them from proteolytic enzymes, and improves their pharmacokinetic profile. (Harris, et al. Nat. Rev. Drug Discov. 2003, 2 (3), 214-221.) The advantages stemming from PEGylation led to the development of novel and effective medicines, such as PEG-Intron® (PEGylated Interferon alpha-2b) and Pegasys® (PEGylated Interferon alpha-2a) for the treatment of Hepatitis C. (Veronese, et al. Drug Discov. Today 2005, 10 (21), 1451-1458.)
PEGylation has also been used to improve small molecule drug delivery, for example, in chemotherapy. Among PEGylated cancer drug candidates is camptothecin, for which PEGylated versions show modestly enhanced circulation time and reduced side effects. (Greenwald, et al. Bioorg. Med. Chem. 1998, 6 (5), 551-562.) PEGylated camptothecin, reported by Enzon, Inc. as Prothecan®, consists of a 40,000 g/mol PEG chain with camptothecin at each chain-end, connected by ester linkages at the C-20-OH position of the drug. Another chemotherapeutic agent, doxorubicin (DOX), has also been improved by PEGylation, including by linear PEG conjugation, for example, as well as through sophisticated architectures such as “bow-tie” dendrimers, with the resulting DOX-polymer therapeutic displaying increased water solubility, decreased toxicity, and enhanced specificity due to the action of the EPR effect. (Rodrigues, et al. Bioorg. Med. Chem. 1999, 7 (11), 2517-2524; Lee, et al. Proc. Natl. Acad. Sci. U.S.A. 2006, 103 (45), 16649-16654.)
Novel polymer-drug conjugates and methodologies for effective polymer conjugation, however, continue to be a critical unmet need and are strongly desired for improving human health through more effective treatment of cancer and other diseases.